tbuckley/cabot-search huggingface dataset:
Real-world progression-free survival (rwPFS) and time to next line of therapy (TTNT) as intermediate endpoints for survival in metastatic breast cancer: A real-world experience.
Authors: Chris Labaki, Ziad Bakouny, Thibaut Sanglier, Andrew Lachlan Schmidt, Jinjoo Shim, David A. Braun, Fanny Bouquet, Maureen Ann Joyce, Wanling Xie, Sara M. Tolaney, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2022)

6520 Background: Real-world progression-free survival (rwPFS) and time to next line of therapy (TTNT) are two endpoints of clinical interest in patients with metastatic breast cancer (MBC). Their validation as intermediate endpoints for overall survival (OS), in a real-world setting, remains not fully established. Methods: We conducted a retrospective cohort study using the nationwide US Electronic Health Record-derived de-identified Flatiron Health database. The study population included pts diagnosed with MBC from Jan 1, 2011 to Feb 30, 2021. rwPFS was defined as the time from start of first-line systemic therapy for MBC to disease progression or death. TTNT was defined as the time from start of first-line systemic therapy until start of next line of therapy. The nonparametric Kendall tau correlation between each surrogate endpoint (rwPFS and TTNT) and OS was evaluated using the Hougaard copula model in the Weibull margin distribution. Kendall’s tau (τ) with its 95%CI was calculated across the entire dataset, and within each disease subgroup defined by receptor (ER and/or PR status defined as hormone receptor [HR], and HER2) status. This work was conducted on behalf of the imCORE network and the Dana-Farber Cancer Institute. Results: Overall, 9,770 patients with MBC were included. Median age was 63 years (IQR: 54-72 years). HR+/HER2- disease represented the most frequent MBC subtype (n=6,287; 64.4%), followed by HER2+ (n=2,096; 21.5%) and triple negative (n=1,387; 14.2%) disease. Median f/u was 41.5 months (95%CI: 40.4 to 42.8). Median OS in the overall population was 32.4 months (95%CI: 31.2 to 33.3). Median rwPFS was 11.5 months (95%CI: 11.1 to 11.9), and median TTNT was 11.1 months (95%CI: 10.7 to 11.5). Across the entire population, the correlation of rwPFS with OS was 0.54 (95%CI: 0.53-0.56), while the correlation of TTNT with OS was 0.47 (95%CI: 0.46-0.48) (Table). Conclusions: rwPFS and TTNT may represent meaningful intermediate endpoints for OS in patients with MBC overall, and within the different disease subgroups. [Table: see text]
Long-term outcomes in patients with advanced urothelial carcinoma (UC) who received avelumab first-line (1L) maintenance with or without second-line (2L) treatment: Exploratory analyses from JAVELIN Bladder 100.
Authors: Joaquim Bellmunt, Thomas Powles, Miguel Angel Climent Duran, Srikala S. Sridhar, Howard Gurney, Nuno Costa, Alessandra Di Pietro, Bo Huang, Shilpa Gupta, Petros Grivas
Journal: Journal of Clinical Oncology (2022)

4560 Background: Avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC that had not progressed with 1L platinum-based chemotherapy (median OS, 23.8 vs 15.0 months; HR, 0.76 [95% CI, 0.631-0.915]; 2-sided p = 0.0036). Avelumab 1L maintenance is now considered standard of care per international guidelines. However, data on outcomes in pts who receive 2L treatment after avelumab 1L maintenance are limited. We report a descriptive analysis of outcomes in pts enrolled in the avelumab + BSC arm of the JAVELIN Bladder 100 trial based on receipt of 2L treatment. Methods: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin. Pts were randomized 1:1 to receive avelumab + BSC or BSC alone. Exploratory analyses of time from randomization to end of 2L treatment and OS were performed in the avelumab + BSC arm in subgroups defined by 2L treatment administered by investigators after discontinuation of study treatment. Results: In the avelumab + BSC arm (n = 350), median follow-up at data cutoff (June 4, 2021) was 38.0 months. 185 pts (52.9%) had discontinued avelumab 1L maintenance treatment for any reason and received 2L treatment, whereas 122 (34.9%) had discontinued avelumab and did not receive 2L treatment. Median OS (95% CI) in subgroups is shown in the Table. In 43 pts (12.3%) who were still receiving avelumab, median treatment duration was 154.6 weeks (range, 106.7-216.0). Among pts who received 2L treatment, median time from end of avelumab 1L maintenance to start of 2L treatment was 1.35 months (range, 0.3-30.9) and median time from randomization to end of 2L treatment was 11.7 months (95% CI, 9.7-13.8). 2L treatment comprised rechallenge with platinum-based chemotherapy in 75 pts (21.4%) or other 2L treatment in 110 pts (31.4%), including 2L anti–PD-(L)1 therapy in 11 pts (3.1%). Additional data based on different types of 2L treatment will be presented. Conclusions: In this exploratory analysis from the JAVELIN Bladder 100 trial with extended follow-up, approximately 60% of pts (185/307 pts) who had discontinued avelumab received 2L treatment. Long-term OS was observed in pts who received avelumab 1L maintenance with or without 2L treatment. Clinical trial information: NCT02603432. [Table: see text]
A phase Ib, open-label, multi-cohort study of metronomic capecitabine plus camrelizumab for treatment of refractory solid tumor: McCrest trial.
Authors: Chenfei Zhou, Chengfang Shangguan, Wenqi Xi, Hui Yang, Liting Guo, Min Shi, Qu Cai, Jun Ji, Yan Shi, Jing Liu, Zhenggang Zhu, Jun Zhang
Journal: Journal of Clinical Oncology (2022)

e16079 Background: The efficacy of immune checkpoint inhibitors (ICIs) monotherapy for refractory solid tumor is relatively poor. Combination therapy is an effective strategy to improve its efficacy. Metronomic chemotherapy that can modulate tumor immunomicroenvironment is a potential partner for ICIs, which is also well-tolerated and low-cost. Methods: This was a phase Ib, open-label, single-center, multi-cohort study designed to evaluate the safety and efficacy of camrelizumab combined with metronomic capecitabine for refractory solid tumors. Patients who were disease progression after standard treatment could be enrolled. PD-L1 status was not compulsory. Capecitabine was administrated orally at 500mg bid every day, with camrelizumab at 200mg IV on Day 1 of a 14-day cycle. Primary endpoint was adverse events (AEs). Secondary endpoints including progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR). The exploratory endpoint was also set to identify the potential molecular alterations during treatment by liquid biopsy analysis. Results: As of December 12, 2021, 19 patients were enrolled including gastric cancer (8), esophageal cancer (6), pancreatic cancer (2), cholangiocarcinoma (2) and duodenal cancer (1). Ten patients had 2 or more prior lines of therapy. The common treatment-related AEs including reactive cutaneous capillary endothelial proliferation (10/19), fatigue (9/19), leukemia (5/19), anemia (5/19), hyponatremia (4/10) and blood bilirubin increased (4/19). Grade 3 AEs including fatigue (2/19) and bronchitis (1/19), and no grade 4 AEs was observed. Three patients suffered severe AEs, including bowel perforation (1), bowel obstruction (1) and bleeding (1), which were all treatment unrelated. There were 4 patients still under treatment, and median number of treatment cycle was 4 (1-16 cycles). The median PFS and OS was 2.1 months (95%CI 1.9-2.3 months) and 5.1 months (95%CI 1.6-8.5 months) respectively. Partial response was observed in 1 esophageal cancer patient with PD-L1 TPS &lt; 1. For 12 patients with assessable lesions, the DCR was 41.6% (5/12). Peripheral blood samples were collected during treatment, and molecular alterations after administration of metronomic capecitabine and camrelizumab were under analysis. Conclusions: The combination of metronomic capecitabine plus camrelizumab was well tolerated in patients with refractory solid tumors. Its efficacy should be assessed in further study. Clinical trial information: NCT04508686, NCT04510818, NCT04932187.
Compartment-specific clinical outcomes in patients with soft tissue sarcomas of the thigh.
Authors: Sei Morinaga, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Hirotaka Yonezawa, Yohei Asano, Shiro Saito, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2022)

e23549 Background: Approximately one-third of all soft tissue sarcomas develop in the thigh, and the risk factors for developing a complication after soft tissue sarcoma resection include the tumour’s location in the lower extremity. This study analysed the relationship between various factors, particularly tumour location and clinical outcome, in patients with primary soft tissue sarcoma of the thigh. Methods: Patients who underwent wide excision of soft tissue sarcomas of the thigh without metastasis at the time of the initial visit between January 2006 and March 2018 were included in the study. Seventy-four patients were included in this retrospective study. The relationships between variables and prognosis were statistically analysed. Results: The mean patient age was 58.7 years (10–86 years), the mean follow-up period was 75 months (24–173 months). A total of 37 tumours were predominantly located in the anterior compartment of the thigh, 17 in the medial compartment, and 20 in the posterior compartment. Multivariate analysis of the patient clinical data demonstrated that seromas developed more often in the medial compartment tumours and postoperative complications excluding seroma occurred more frequently in patients with two or more muscles resected or stage III tumours. A low Musculoskeletal Tumor Society score was associated with a long operative time (more than 120 min), anterior compartment tumours, and more than two muscle resections. In addition, soft tissue sarcomas in the medial compartment and stage III sarcomas were associated with a low 5-year metastasis-free survival. Conclusions: Soft tissue sarcomas in the medial compartment were associated with postoperative seroma and metastasis, whereas sarcomas in the anterior compartment correlated with low postoperative function. Surgeons should be aware of compartment-specific clinical outcomes in patients with soft tissue sarcomas of the thigh.[Table: see text]
Predictive significance of tumor-associated miRNA-21 and -221 expression in patients with prostate cancer.
Authors: Liliya Tryfonyuk, Tetiana Borikun, Taras Zadvornyi, Olha Rossylna, Natalia Pavlukovich
Journal: Journal of Clinical Oncology (2022)

e17015 Background: It is thought that the occurrence and progression of tumors, such as prostate cancer (PCа), may be due to decreased levels of tumor-inhibiting microRNAs and/or overexpression of oncogenic microRNAs, but their specificity and role in tumor progression are contradictory. That is why the study of the possibility of using miRNAs as prognostic markers is especially relevant. Objective: to investigate the features of tumor -associated microRNAs-21 and -221 expression in PCa tissue with different risk of progression and to determine the relationship of their indicators with the molecular profile of tumors. Methods: The study was conducted on the clinical material of 60 patients with PCa stage II-III, who were treated in Rivne Regional Hospital and Rivne oncological center during 2018-2021 years. Determination of the risk of PCa progression was performed by D'Amico et al. (1998). Immunohistochemical study of Ki-67 expression (clone MIB -1) and androgen receptors (AR) (clone 441) were performed on paraffin sections of tumor tissue using the Ultra Vision LP Detection System (Thermo Scientific, USA). Determination of microRNA-21 and -221 levels were determined using real-time quantitative PCR. Statistical processing of the results was performed using GraphPad Prism 8. Results: It is determined that a characteristic feature of PCa with a low risk of progression by D'Amico et al . are low expression of oncogenic miRNA-21 and -221 in tumor tissue. In particular, in the PCa samples of high risk of progression (n = 30) the level of miRNA-21 was 3.2 times (p &lt; 0.05), and miRNA-221 was 1.35 times (p &lt; 0.05) higher compared to tumor tissue of patients with low progression (n = 30). The existence of a direct correlation between the expression of miRNA-21 and the proliferative activity of PCa (ρ = 0.63; p &lt; 0.05) is shown. We found that the expression of miRNA-221 is associated with a high level of AR expression (ρ = 0.43; p &lt; 0.05) . Conclusions: The obtained data indicate the relationship of tumor -associated microRNA-21 and -221 with the risk of tumor progression and such molecular biological characteristics of tumors as proliferative activity and receptor status, which indicates the prospects for their further study as additional markers for predicting of PCa course.
Efficacy and toxicity of carboplatin and gemcitabine dosed on day 1/day 8 versus day 1 alone for platinum-sensitive recurrent epithelial ovarian cancer.
Authors: Erika Joelle Lampert, Peter Graham Rose, Laura Chambers, Meng Yao, Chad Michener, Robert Debernardo
Journal: Journal of Clinical Oncology (2022)

5541 Background: Carboplatin, gemcitabine +/- bevacizumab is a preferred regimen for recurrent, platinum-sensitive ovarian cancer (PSOC). A phase III trial established that the regimen of carboplatin on Day 1 (D1) and gemcitabine on D1 and Day 8 (D8) was associated with acceptable toxicity and improved progression free survival (PFS) compared to carboplatin alone. Treatment with gemcitabine on D8 incurs more exposure to cytotoxic therapy and increased burden on patients and the healthcare system, especially during the COVID-19 pandemic. However, it is unknown whether D1/D8 gemcitabine imparts an improvement in efficacy compared to D1 alone. Our objective was to compare efficacy and toxicity of carboplatin and gemcitabine D1/D8 (CG-D1/8) with a modified D1 regimen (CG-D1). Methods: A retrospective single-institution cohort study was performed in women with recurrent PSOC treated with carboplatin, gemcitabine +/- bevacizumab from 2009-2020. Data was analyzed by intention to treat comparing women who received CG-D1/8 vs CG-D1. Data was also analyzed by 3 groups: CG-D1/8 vs CG-D1/8 but dropped D8 vs CG-D1. The primary endpoint was response rate (RR), defined as complete or partial response at 6 cycles or maximum cycles if &lt;6. Secondary outcomes included PFS, overall survival (OS), toxicity, Neulasta use and dose reduction. Results: Of 200 patients, 26% completed CG-D1/D8, 21.5% started CG-D1/D8 but dropped D8, and 52.5% received CG-D1. There were no significant differences in age, race, or ECOG between cohorts. Among CG-D1/D8, 45.3% dropped D8 primarily due to neutropenia (51.2%) or thrombocytopenia (30.2%). The RR at 6 cycles was 68.7% for CG-D1/8 completed, 70.7% for CG-D1/8 dropped D8, and 69.3% for CG-D1 (p=0.97). The median PFS was 13.1, 12.1 and 12.4 months for CG-D1/8 completed, CG-D1/8 dropped D8, and CG-D1, respectively (p=0.29). Similarly, median OS was 28.2, 33.5 and 34.3 months for the above groups respectively (p=0.42). While there was no difference in concurrent bevacizumab use for CG-D1/8 and CG-D1 (34.7% vs 29.5%, p=0.43), among the CG-D1/8 patients, a significantly higher proportion of patients who dropped D8 received bevacizumab (51.2% vs 21.2%, p=0.006). Table 1 lists secondary outcomes. Conclusions: There was no significant difference in RR, PFS or OS among women with PSOC receiving CG-D1/8 vs CG-D1, regardless of whether D8 was dropped. CG-D1/8 was associated with significantly greater hematologic toxicity. These findings suggest a modified D1 regimen may be a suitable alternative to standard CG-D1/8 treatment and warrant prospective validation. [Table: see text]
A phase II trial of TGFβ type I receptor inhibitor, galunisertib, plus neoadjuvant chemoradiation in patients with locally advanced rectal cancer.
Authors: Kristina Hoot Young, Andrew J Gunderson, Miranda Gilchrist, Mark Whiteford, Maria X Kiely, Amanda Hayman, David P O'Brien, Rehan Ahmad, Jeffrey V Manchio, Evelyn Brosnan, Gina M. Vaccaro, Rui Li, Miklos Simon, Mary McCormick, Ashley Drokin, Julie Cramer, Walter John Urba, Michael Gough, Marka R. Crittenden, Tomoko Yamazaki
Journal: Journal of Clinical Oncology (2022)

3617 Background: Transforming growth factor beta (TGFβ) is an immunosuppressive cytokine upregulated in colorectal cancer. Preclinical data demonstrated improved response to chemoradiation with TGFβ blockade in colorectal adenocarcinoma. Here we report the results of our single arm Phase II study combining the TGFβ type I receptor kinase inhibitor, galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal adenocarcinoma. Methods: Eligible patients had T3+ or N+ rectal adenocarcinoma planned for surgical resection. Enrolled patients completed a 14-day course of galunisertib, followed by chemoradiation with continuous infusion 5-fluorouracil or capecitabine with radiation to 50.4-54Gy in 28-30 fractions. On day 30, patients underwent another 14-day course of galunisertib concurrent with ongoing chemoradiation. Five to nine weeks after completing neoadjuvant therapy, patients underwent response assessment. Those with complete response by physical exam, proctoscopy, and MRI, could opt for non-operative management and proceed to mFOLFOX6. Those with less than a complete response underwent surgical resection. The primary endpoint was complete response rate (CR), which was a composite of pathologic complete responses in those patients who proceeded to surgery, and clinical complete responses maintained at 1 year after completion of therapy for those who chose non-operative management. Using a Simon Two-Stage approach with 90% power and α = 0.05, to detect a 20% improvement in complete response rate compared to historical control (15% vs 35%); we reject the null hypothesis if ≥10/38 patients have a CR. 38 patients were enrolled with 35 patients evaluable. Results: Median age was 51y, 68% of patients were male, 87% of patients were Stage III, 97% of patients were node-positive, and 97% were proficient in mismatch repair. 95% of patients completed study therapy. Toxicity attributed to galunisertib was Grade 1-2. 28 patients went to surgery, with a mean neoadjuvant rectal (NAR) score (NAR = 5pN-3(cT-pT)+12] 2 /9.61) of 11.29, and pCR in 7 patients. 7 patients underwent non-operative management, with 5 achieving cCR at 1 year. Therefore, complete responses were observed in 12 patients. Peripheral immune monitoring revealed percent change in CD3+CD4-CXCR3+ T cells and activated CD8 EM T cells correlated with response to therapy. 2y PFS and OS were 81.5% and 97%. Conclusions: The addition of TGFβ inhibition to neoadjuvant chemoradiation in locally advanced rectal cancer markedly improved response to therapy, was well tolerated, and warrants further investigation. Clinical trial information: NCT02688712.
Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and to better predict intracranial tumor response in patients with non–small cell lung cancer with brain metastases: A prospective cohort study.
Authors: Meichen Li, Xue Hou, Jing Chen, Baishen Zhang, Juan Yu, Na Wang, Delan Li, Yang Shao, Dongqin Zhu, Chuqiao Liang, Qiuxiang Ou, Yutong Ma, Likun Chen
Journal: Journal of Clinical Oncology (2022)

2023 Background: Cerebrospinal fluid (CSF) can be used as a type of liquid biopsy to detect brain tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor response and monitor mutational evolution during systemic treatment in non-small cell lung cancer (NSCLC) patients with brain metastases. Methods: We conducted aprospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and at disease progression. Primary extracranial tumor samples were available for 58 patients and all samples underwent targeted next generation sequencing of 425 cancer-related genes. Results: At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of heterogeneity was observed between paired CSF and plasma samples, while concordance in driver mutations was also observed. A higher number of unique copy number variations (CNVs) were detected in CSF ctDNA than in plasma. CtDNA-positivity in baseline CSF samples was associated with poor outcomes (HR = 2.565, P = 0.003). Moreover, patients with increased concentrations of ctDNA in CSF after 8 weeks of treatment had significantly shorter intracranial progression-free survivals (PFS) than patients with decreased concentrations of CSF ctDNA (6.13 months vs 13.27 months, HR = 3.92, P = 0.007). Increased concentrations of plasma ctDNA were associated with shorter extracranial PFS (6.13 months vs 11.57 months, HR = 2.626, P = 0.032). From clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of systemic treatment. The clonal mutations remained more than 80% in CSF after 8-weeks of treatment also predicted a shorter intracranial PFS (HR = 3.785, P = 0.039). Conclusions: CSF ctDNA revealed unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor response and track clonal evolution during treatment in NSCLC patients with brain metastases.